This invention relates to method of use of inhibitors of cholesteryl ester transfer protein (CETP) in subjects with high triglyceride level, for raising certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and for lowering other plasma lipid level, such as low density lipoprotein (LDL)-cholesterol and accordingly for the treating diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol, such as atherosclerosis, dyslipidemia and cardiovascular diseases.
Atherosclerosis and its clinical consequences, coronary heart disease, is the leading cause of mortality in the industrialized world. It has long been recognized that variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and coronary heart disease. While elevated LDL-C may be the most recognized form of dislipidemina, low HDL-C is also a known risk factor for coronary heart disease.
Metabolic control of lipoprotein levels is a complex and dynamic process involving many factors. Among the many factors, one important metabolic control in man in the cholesteryl ester transfer protein (CETP).
CETP is a 74KD glycopeptide, it is secreted by the liver and is a key player in facilitating the transfer of lipids between the various lipoproteins in plasma. The primary function of CETP is to redistribute cholesteryl esters (CE) and triglycerides between lipoprotein particle, including high density lipoproteins (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and chylomicrons. See Assmann, G et al., “HDL cholesterol and protective factors in atherosclerosis,” Circulation, 109: 1118-1114 (2004). The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile has been shown to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for coronary heart disease. Numerous epidemiologic studies correlating the effects of natural variation of CETP activity with respect to coronary heart disease risk have been performed (See Hirano, K. I. et al. (2000), “Pros and Cons of inhibiting cholesteryl ester transfer protein”, Curr. Opin. Lipidol. 11(6), 589-596). These studies have clearly demonstrated an inverse correlation between plasma HDL-C concentration and CETP activity (see Inazu A., et al. (2000), “Cholesteryl ester transfer protein and atherosclerosis”, Curr. Opin. Lipidol. 11(4), 389-396), leading to the hypothesis that pharmacologic inhibition of CETP lipid transfer activity is beneficial to humans in increasing levels of HDL-C while lowering those of LDL.
Anacetrapib, a CETP inhibitor developed by Merck, is currently in Phase III clinical development for the treatment of dyslipidemia and coronary heart disease. In vitro data indicate that anacetrapib does not retain its potency of CETP inhibition in plasma obtained from subjects with elevated triglyceride levels. This may translate into reduced efficacy of anacetrapib in patients with high triglycerides, whom constitute a significant portion of dyslipidemic subjects. Overall, 31% of the adult US population has an elevated plasma triglyceride concentration (≧150 mg/dL) (Carroll MD. Trends in serum lipids and lipoproteins of adults, 1960-2002. Journal of the American Medical Association 2005; 294:1773-81). High (≧200 mg/dL) and very high (≧500 mg/dL) fasting triglyceride levels are found in 16.2% and 1.1% of adults, respectively. Therefore, there is a clear need for improved therapy for the treatment and prevention of diseases and conditions related to CETP activity in a patient with high plasma triglycerides. To date, Merck has not provided any information on the efficacy of Anacetrapib in patients stratified by plasma triglyceride concentration.